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Proper replacement or repair of damaged tendons or ligaments requires functionally engineered tissue that mimics their native mechanical properties. While tendon structure–function relationships are generally assumed, there exists little quantitative evidence of the roles of distinct tendon components in tendon function. Previous work has used linear correlations to assess the independent, univariate effects of one structural or one biochemical variable on mechanics. The current study's objective was to simultaneously and rigorously evaluate the relative contributions of seven different structural and compositional variables in predicting tissue mechanical properties through the use of multiple regression statistical models. Structural, biochemical, and mechanical analysis were all performed on tail tendon fascicles from different groups of transgenic mice, which provide a reproducible, noninvasive, in vivo model of changes in tendon structure and composition. Interestingly, glycosaminoglycan (GAG) content was observed to be the strongest predictor of mechanical properties. GAG content was also well correlated with collagen content and mean collagen fibril diameter. Collagen fibril area fraction was a significant predictor only of material properties. Therefore, in a large multivariate model, GAG content was the largest predictor of mechanical properties, perhaps both through direct influence and indirectly through its correlation with collagen content and fibril structure. [ABSTRACT FROM AUTHOR]

Tendons have complex mechanical behaviors that are viscoelastic, nonlinear, and anisotropic. It is widely held that these behaviors are provided for by the tissue’s composition and structure. However, little data are available to quantify such structure–function relationships. This study quantified tendon mechanical behaviors, including viscoelasticity and nonlinearity, for groups of mice that were genetically engineered for altered extracellular matrix proteins. Uniaxial tensile stress-relaxation experiments were performed on tail tendon fascicles from the following groups: eight week old decorin knockout, eight week old reduced type I collagen, three week old control, and eight week old control. Data were fit using Fung’s quasilinear viscoelastic model, where the model parameters represent the linear viscoelastic and nonlinear elastic response. The viscoelastic properties demonstrated a larger and faster stress relaxation for the decorin knockout and a smaller and slower stress relaxation for the three week control. The elastic parameter, A, in the eight week control group was significantly greater than in the collagen reduction and three week control groups. This study provides quantitative evidence for structure–function relationships in tendon, including the role of proteoglycan in viscoelasticity. Future studies should directly correlate composition and structure with tendon mechanics for the design and evaluation of tissue-engineered constructs or tendon repairs. © 2003 Biomedical Engineering Society. PAC2003: 8719Rr, 8715La, 8714Ee, 8710+e [ABSTRACT FROM AUTHOR]

Decorin is a member of the small leucine-rich proteoglycan gene family and plays an important role in suppressing cancer cell growth and metastasis. To elucidate the importance of decorin in intestinal carcinogenesis, a decorin-deficient (Dcn−/−) mouse model was employed. We found that targeted inactivation of decorin was sufficient to cause intestinal tumor formation with 30% of the Dcn−/− mice developing intestinal tumors with no other chemical or genetic initiation. Moreover, a high-risk diet amplified and accelerated the tumors initiated by decorin deficiency. Further, tumorigenesis in Dcn−/− mice was associated with disruption of intestinal maturation, including decreased cell differentiation and increased proliferation, which were linked to the downregulation of p21WAF1/cip1, p27kip1, intestinal trefoil factor and E-cadherin and to the upregulation of β-catenin signaling. In addition, we found that decorin was highly expressed in the differentiated area of human normal colonic mucosa, but was dramatically reduced in paired colorectal cancer tissues. Taken together, our data demonstrate that decorin acts as a tumor suppressor gene and plays an important role in the maintenance of cell maturation and therefore homeostasis in the intestinal tract. [ABSTRACT FROM AUTHOR]

FEZ1/LZTS1 is a tumor suppressor gene that is frequently altered in human cancers of different histotypes. We have reported previously that LZTS1 is downregulated in high-grade bladder cancer and that its restoration suppresses tumorigenicity in urothelial carcinoma cells. To further investigate the role of LZTS1 in the development of bladder cancer, we utilized heterozygous and nullizygous Lzts1 mice in a chemically induced carcinogenesis model. Fifty-eight mice consisting of 25 Lzts1+/+, 17 Lzts1+/− and 16 Lzts1−/− were treated with N-butyl-N-(4-hydroxybutil) nitrosamine (BBN). Results showed that there was a significant increase in neoplastic lesions in the Lzts1+/− (82.3%) and Lzts1−/− (93.8%) versus Lzts1+/+ (8.0%) mice after BBN treatment. No difference in cancer incidence between Lzts1+/− and Lzts1−/− was observed. Collectively, these findings indicate that loss of one or both LZTS1 alleles hampers the normal defenses of urothelial cells against carcinogens, favoring bladder cancer development. Therefore, LZTS1 may become an excellent target for gene therapy in advanced bladder carcinoma. [ABSTRACT FROM AUTHOR]